Human induced pluripotent stem cell–derived extracellular vesicles reduce hepatic stellate cell activation and liver fibrosis

Povero, Davide; Pinatel, Eva; Leszczynska, Aleksandra; Goyal, Nidhi; Nishio, Toshikazu; Kim, Jihoon; Kneiber, David Boulos; Horcel, Lucas de Araujo; Eguchi, Akiko; Ordonez, Paulina; Kisseleva, Tatiana; Feldstein, Ariel E.

doi:10.1172/jci.insight.125652

Cited by 87 publications

(97 citation statements)

References 45 publications

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“…However, no effect was observed in the lipid accumulation [95]. Similar anti-fibrosis effects on HSCs are shown in the other studies of EVs isolated from induced pluripotent stem cells (iPSC) [96], amnion-derived MSCs (AMSCs) [97], human liver stem cells (HLSCs) [98], and human umbilical cord-derived MSCs [99]. This evidence of hepatic protectiveness effects by the EVs is important, as the same effects were also seen before with MSCs (cells) treatment in various liver injury models due to bacterial lipopolysaccharide [100], thioacetamide (TAA) [101], ischemia/reperfusion [102], radiation [103], and D-galactosamine [104].…”

Section: Evs From the Mesenchymal Stem Cells As A Treatment Optionsupporting

confidence: 78%

Extracellular Vesicles in the Development of the Non-Alcoholic Fatty Liver Disease: An Update

et al. 2020

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Non-alcoholic fatty liver disease (NAFLD) is a broad spectrum of liver damage disease from a simple fatty liver (steatosis) to more severe liver conditions such as non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Extracellular vesicles (EVs) are a heterogeneous group of small membrane vesicles released by various cells in normal or diseased conditions. The EVs carry bioactive components in their cargos and can mediate the metabolic changes in recipient cells. In the context of NAFLD, EVs derived from adipocytes are implicated in the development of whole-body insulin resistance (IR), the hepatic IR, and fatty liver (steatosis). Excessive fatty acid accumulation is toxic to the hepatocytes, and this lipotoxicity can induce the release of EVs (hepatocyte-EVs), which can mediate the progression of fibrosis via the activation of nearby macrophages and hepatic stellate cells (HSCs). In this review, we summarized the recent findings of adipocyte- and hepatocyte-EVs on NAFLD disease development and progression. We also discussed previous studies on mesenchymal stem cell (MSC) EVs that have garnered attention due to their effects on preventing liver fibrosis and increasing liver regeneration and proliferation.

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Section: Evs From the Mesenchymal Stem Cells As A Treatment Optionsupporting

confidence: 78%

Extracellular Vesicles in the Development of the Non-Alcoholic Fatty Liver Disease: An Update

et al. 2020

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“…Although we did not rule out the possibility that it might be the direct protective effect of hUCMSC-EVs on liver cells or the indirect effects target on the other cells, e.g., macrophages or T cells, our data suggested that hUCMSC-EV-meditated suppression of TGF-β1-induced HSC activation may be involved in the amelioration of liver fibrosis in schistosomiasis. It was reported recently that the administration of human-induced pluripotent stem cell-derived EVs reduces development of fibrosis and TGF-β1induced HSC activation in an experimental model of cholestatic liver fibrosis [36]. In contrast, some published studies have indicated that adipose MSC-EVs (AMSC-EVs) had no demonstrable effect on the proliferation or activation of HSCs [37,38].…”

Section: Discussionmentioning

confidence: 99%

hUCMSC-extracellular vesicles downregulated hepatic stellate cell activation and reduced liver injury in S. japonicum-infected mice

Dong

Chen

et al. 2020

Stem Cell Res Ther

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Background: Accumulating evidence shows that mesenchymal stem cells (MSCs) have the potential as a cellular therapy avenue for schistosome-induced liver injury. Extracellular vesicles (EVs) are membranous vesicles released by almost all cell types, and EVs produced by MSCs (MSC-EVs) exert therapeutic effects in several disease models. However, the potential of MSC-EVs in schistosomiasis treatment remains unclear. Methods: Using survival analysis, HE and Masson's trichrome staining, immunohistochemical, western blot analysis, real-time PCR, and EdU proliferation, we investigated the effects of human umbilical cord MSC-derived EVs (hUCMSC-EVs) on the survival and liver injury in the S. japonicum-infected mice and explored the underlying mechanism. Results: Here, we found that like hUCMSCs, hUCMSC-EVs significantly ameliorated liver injury and improved the survival of schistosome-infected mice. Indeed, the hUCMSC-EV-mediated alleviation of liver injury is associated with decreased expression of α-smooth muscle actin (α-SMA), collagen 1, and collagen 3. More importantly, we showed that hUCMSC-EVs directly suppressed the proliferation of LX2 (human hepatic stellate cell) in vitro. In addition, hUCMSC-EVs significantly downregulated the activation of LX2 after transforming growth factor-β1 (TGF-β1) treatment. Conclusion: Our results provided the first evidence that hUCMSC-EVs reduced liver injury in S. japonicum-infected mice, potentially creating new avenues for the treatment of liver damage in schistosomiasis.

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“…iPSC-EVs (about 300 nm) also reduced hepatic stellate cell activation and liver fibrosis, showing the ability to decrease profibrogenic markers a-smooth muscle actin, collagen Ia1, and fibronectin, and tissue inhibitor of metalloproteinases-1. 71 Genomics analysis of miRNA cargo of iPSC-EVs showed 22 highly expressed miRNAs, and miR-92a-3p was found to be the most abundant one. In particular, iPSC-EVs were reported to reduce ROS levels of senescent MSCs, improve the growth of replicatively aged MSCs, and alleviate cellular aging in a genetically induced senescent model, in part, by delivering intracellular peroxiredoxin antioxidant enzymes (e.g., PRDX1 and PRDX2).…”

Section: Ipsc-derived Evs/exosomesmentioning

confidence: 99%

Human Pluripotent Stem Cell-Derived Extracellular Vesicles: Characteristics and Applications

Jeske

Bejoy

Marzano

et al. 2020

Tissue Engineering Part B: Reviews

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Extracellular vesicles (EVs), including exosomes and microvesicles, are found to play an important role in various biological processes and maintaining tissue homeostasis. Because of the protective effects, stem cellderived EVs can be used to reduce oxidative stress and apoptosis in the recipient cells. In addition, EVs/ exosomes have been used as directional communication tools between stem cells and parenchymal cells, giving them the ability to serve as biomarkers. Likewise, altered EVs/exosomes can be utilized for drug delivery by loading with proteins, small interfering RNAs, and viral vectors, in particular, because EVs/exosomes are able to cross the blood-brain barrier. In this review article, the properties of human induced pluripotent stem cell (iPSC)-derived EVs are discussed. The biogenesis, that is, how EVs originate in the endosomal compartment or from the cell layer of microvesicles, EV composition, the available methods of purification, and characterizations of EVs/exosomes are summarized. In particular, EVs/exosomes derived from iPSCs of different lineage specifications and the applications of these stem cell-derived exosomes in neurological diseases are discussed.

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Human induced pluripotent stem cell–derived extracellular vesicles reduce hepatic stellate cell activation and liver fibrosis

Cited by 87 publications

References 45 publications

Extracellular Vesicles in the Development of the Non-Alcoholic Fatty Liver Disease: An Update

Extracellular Vesicles in the Development of the Non-Alcoholic Fatty Liver Disease: An Update

hUCMSC-extracellular vesicles downregulated hepatic stellate cell activation and reduced liver injury in S. japonicum-infected mice

Human Pluripotent Stem Cell-Derived Extracellular Vesicles: Characteristics and Applications

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